The present invention relates to an improved process for the production of 9-(.beta.-D-arabinofuranosyl) adenine, 5'-phosphate.
9-(.beta.-D-arabinofuranosyl)adenine, 5'-phosphate, is useful as a medicinal agent, especially as an antiviral agent, being active against Herpes simplex virus as described in U.S. Pat. No. 3,703,507. The compound is also known as Vira-MP.RTM. or Vidarabine monophosphate. Since early publication of 9-(.beta.-D-arabinofuranosyl)adenine [Vidarabine, also known as Vira-A.RTM.] as an antiviral agent in Adams H. G., et al, Journal of Infectious Diseases 1976;133(Suppl):A151-A159, and Pharmacology & Therapeutics 1980;8:143-171 by Buchanan R. A. and Hess F., medical interest remains active in Vidarabine and derivatives, for example, a recent study by Whitley R., et al in the New England Journal of Medicine 1991;32(7):444-9 comparing Vidarabine and Acyclovir found "In this multicenter, randomized, blinded study there were no differences in outcome between Vidarabine and Acyclovir in the treatment of neonatal herpes simplex virus infection".
U.S. Pat. No. 3,703,507 discloses a process for preparing 9-(.beta.-D-arabinofuranosyl)adenine, 5'-phosphate, by reacting 9-(.beta.-D-arabinofuranosyl) adenine with phosphorus oxychloride in glacial acetic acid in the presence of a tertiary amine base.
U.S. Pat. No. 3,413,282 discloses a process for converting a nucleoside to a 5'-nucleotide phosphate by reaction with phosphorus oxychloride or diphosphoryl chloride (tetra-chloropyrophosphate) in the presence of trialkyl phosphate solvent. The reactive product is hydrolyzed, neutralized, and the 5'-nucleotide phosphate isolated by absorption and elution techniques requiring activated carbon or ion exchange resin. The methods disclosed in U.S. Pat. Nos. 3,703,507 and 3,413,282 involve undesirable time-consuming manipulations and processing steps as well as requiring costly separation media and elution solvents.
U.S. Pat. No. 4,123,609 discloses a process for preparing 9-(.beta.-D-arabinofuranosyl)adenine, 5'-phosphate. The process involves reaction of 9-(.beta.-D-arabinofuranosyl)adenine with a phosphorylating agent such as a phosphorus oxyhalide, in particular phosphorus oxychloride, phosphorus oxybromide, and diphosphoryl chloride in the presence of trialkyl phosphate solvent. Subsequently, the reaction mixture is hydrolyzed; the pH of the aqueous hydrolysis mixture is adjusted to the basic side of the pH scale to cause separation into aqueous and nonaqueous liquid phases; the trialkyl phosphate solvent is removed from the aqueous mixture while maintaining the residual aqueous mixture at a pH at which the ester product is insoluble to cause the ester product to precipitate as a solid phase from the aqueous mixture; and isolating the product. Although this process provides the desired 9-(.beta.-D-arabinofuranosyl)adenine, 5'-phosphate, it is difficult to conduct on large-scale. The yields are modest on industrial or large scale, about 55%, and the product formed is a waxy and/or gummy solid that is difficult to isolate and that could not be readily separated from the inorganic salts produced except by ion-exchange chromatography.
The object of the present invention is an improved process for preparing 9-(.beta.-D-arabinofuranosyl)adenine, 5'-phosphate.
The present process is a more specific and scalable process for the production of 9-(.beta.-D-arabinofuranosyl)adenine, 5'-phosphate, and affords higher yields compared to the previous methods.